| Objective:Acememtacin is a kind of new generation of non-steroidal anti-inflammation drugs which is first time marketed in pro-federal Germany,and not belong to the group of steroid.Its normal dosage have some serious side-effects such as short of half-life and reaction of stomach which lead to the non-convenience of clinical medication and the instability of clinical effect.A new formulation of acemetacin sustained-release tablet would be developed in order to reduce above side-effects caused by acemetacin conventional dosage.Methods:At the background of literatre and force-experiment, first of all,taking lactose ,starch,CC-Na and PVP as four influencial factors,choosing three different levels respectively,we use L9 (34)orthogonal design to analysis the score result and select the optimum formulation of tablet fast-release part.The disintegration-time were used as evaluation standard.On the basis of pilot experiment and literature, we decide the main reasons which affect sustained-release part release drugs are technique factors(tablet hard degree,particles size),release factors(pH,the conbolution-speed,dissolve method), the kind and amount of blocker and the concentration of ethanol.The release behavior of sustained-release tablet was studied by cylindrical basket method.The release medium is pH6.8 KH2PO4-NaOH,and temperature is 37±1℃,samples were obtained 0.5,1,2,3,4,5,6,8,10,12h and quantitated at 254nm by Ultraviolet spectrophotometer.We calculate the concentration of acemetacin by standard curve,and then get the accumulative release percentage of the sustained-release tablet.Three batches of sustained-release tablets were prepared and studied through release experiment to confirm the stability of formulation.The release data were analyzed by three model.The chemical and physical stability of the optimal formulation of acemetacin was investigated,including stress tesing(high humidity testing,optical testing,high temperature testing)and long-term testing.The related substances in acemetacin can be separated and determined by HPLC with Ultraviolet detector.The liquid Chromatograph is equipped with a 254nm detector and a Kromasil C8 colum.Mobile phase is a suitable filtered mixture of methylacohol-HAC(80:20).The flow rate is about 1.0ml per minuter.6 rabbits were divided into 2 groups.One group was given sustained-release tablet,and the other was given market capsules. Blood serum sample were obtained at different time.A HPLC method were developed to determine acemetacin concentration in rabbit,s blood serum.Results: The results of orthogonal experiment design were found.The optimal formalution of fast-release part is A2B1C1D2.Then the optimal formulation of sustained-release part is decided.Three batches of sustained-release tablets were prepared according to the optimal formulation.The release data were analyed by three model :Higuchi equation,zero order kinetics,first order kintics,the release property more conformed to Higuchi equation.The correlation of linear range was good between 3-30ug/ml,C=23.57497A-0.26325,(r=0.99993). The recoveries were 99.36%, 99.23%, 100.04%, 99.33%, 99.40%, 99.28%,RSD:0.30%,respectively,RSD:0.90%,1.27%,1.52%.Isolation of related compounds and acemetacin could be completely separated.The result of the stress testing showed that acemetacin did not change.High humidity(90%±5%) made the weights increase more than 5% after 5 days.The result of pharmacokinetics in rabbit showed that the sustained-release tablet and market capsules all conformed to one-compartment model.The result of t-test showed that there was not difference pharmacokinetic parameters.Conclusion:The result of release experiment in vitro and pharmacokinetic study in rabbits showed that sustained-release tablets possessed the obvious properities of sustained-release preparation in vitro and in vivo.
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